Metabolic Syndrome Consequent to Endocrine Disorders

V. Popovic, M. Korbonits, V., Popovic, M., Korbonits, Federica Guaraldi, Giovanni Corona, Federica, Guaraldi, Giovanni, Corona

• Publisher: S. Karger
• Year: 2018
• Print ISBN: 9783318063349
• eBook ISBN: 9783318063356
• Topic: Medicine
• Subtopic: Nutrition, Dietics & Bariatrics

Hormonal dysfunction can have a major and often complex impact on all key components of the metabolic syndrome. This book comprises state-of-the-art reviews on the subject written by recognized experts in the field of endocrinology. Each chapter covers specific manifestations associated with the metabolic syndrome in classic endocrine diseases. Compelling questions are highlighted and future directions presented. The topics covered include hypopituitarism, adrenal insufficiency, acromegaly, glucocorticoid excess, androgen excess, hypogonadism, prolactin, and thyroid and parathyroid hormone abnormalities. This book is meant to inspire subsequent research related to metabolic complications in endocrine diseases, thus enabling early detection as well as prompt and appropriate management.

Popovic V, Korbonits M (eds): Metabolic Syndrome Consequent to Endocrine Disorders.
Front Horm Res. Basel, Karger, 2018, vol 49, pp 48–66 (DOI: 10.1159/000485996)

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Metabolic Syndrome in Thyroid Disease

K. Alexander Iwen^a · Rebecca Oelkrug^a · Hannes Kalscheuer^a · Georg Brabant^{a, b}

^aMedizinische Klinik I, Experimentelle und Klinische Endokrinologie, Universität zu Lübeck, Lübeck, Germany; ^bDepartment of Endocrinology, The Christie Manchester Academic Health Science Centre, Manchester, UK

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Abstract

Cardiometabolic risk factors like abdominal obesity, hyperglycemia, low high-density lipoprotein (HDL) cholesterol, elevated triglycerides, and hypertension are defined as metabolic syndrome (MetS), which represents one of the most frequent endocrine disorders particularly in a society with increasing weight problems. As more and more evidence is accumulated that thyroid hormones affect components of the MetS, the present review aims to summarize the rapidly expanding knowledge on the pathophysiological interaction between thyroid hormone status and MetS. The review is based on a PubMed search for combinations of thyroid hormone action and MetS, blood pressure, hypertension, hyperlipidemia, cholesterol, HDL cholesterol, glucose, diabetes mellitus, body weight, or visceral fat. A special focus was given for manuscripts published after 2000 but we included seminal papers published before year 2000 as well.

© 2018 S. Karger AG, Basel

Introduction and Definitions

Thyroid disorders and the metabolic syndrome (MetS) represent the most common endocrine disorders, both related to significant morbidity [1, 2]. Thus, any association between the 2 conditions may be purely by chance but accumulated evidence suggests that thyroid hormones (TH) affect glucose metabolism and may induce or aggravate components of MetS. Here, we will review data from animal and human studies to define putative underlying mechanisms of TH-mediated effects on MetS. We will restrict our review to classical TH, in particular triiodothyronine (T3). Emerging new and exciting data of less well studied TH metabolites like diiodothyronine or thyronamines are beyond the scope of this review.

MetS comprises obesity, dyslipidemia, diabetes mellitus, and arterial hypertension. Insulin resistance is the pathophysiological hallmark of MetS but is also frequently associated with (visceral) obesity, generally defined by an increased waist circumference or waist-to-hip ratio. The diagnostic criteria for MetS differ between various international definitions by the (i) International Diabetes Federation, (ii) National Cholesterol Education Program Adult Treatment Panel III, or (iii) World Health Organization [3]. However, the differences are small, and for the scope of the present review, we used the definitions addressed by the studies cited.

The criteria for thyroid disorders followed recent guidelines by the American Thyroid Association and European Thyroid Association on hypothyroidism and hyperthyroidism [4–7]. The definitions of subclinical forms of thyroid dysfunction varied considerably but were used according to the definitions given in the respective citations.

Epidemiological Data/Observational Studies

In a first approach, we reviewed available epidemiological data to evaluate possible relationships between thyroid disorders and MetS. A number of studies have explored this association, but despite relatively high numbers of participants in Europe, North America, and Asia, these studies are hampered by relatively low numbers of individuals meeting the criteria for (i) MetS and (ii) overt thyroid dysfunction.

Cross-sectional studies published within the last decade included euthyroid individuals and patients with subclinical thyroid dysfunction to increase statistical power. Definitions of euthyroidism and subclinical thyroid dysfunctions as well as MetS were heterogenous: most studies employed National Cholesterol Education Program Adult Treatment Panel III criteria, but some modified these for example, ethnic differences [8] or used local criteria [9]. Single components of MetS were addressed in a number of studies, including lipid parameters [10, 11], blood pressure [12], weight, or anthropometric parameters [13–16], while other studies examined all components of the MetS.

Despite these limitations, cross-sectional studies identified significant associations of thyroid function with components of the MetS. More specifically, components were associated with the following: (i) thyroid-stimulating hormone (TSH)-levels [9–32], (ii) low normal free levothyroxine (fT4) concentrations [8, 14, 21–24, 26,27, 33–36], and (iii) high normal fT3 levels [21, 22, 35, 37–40].

Cross-sectional studies provide data at defined time points. Thus, longitudinal/follow-up studies are of particular interest to examine whether changes of TSH or TH concentrations are also associated with changes of the MetS. However, relatively few longitudinal/follow-up studies analyzed TH functions and associations with components of the MetS. Follow-up periods ranged from 3 years [41] to 11 years [42, 43].

Again, a number of analyses were restricted to a single component of the MetS. Changes of TSH levels [42, 44–48] and fT4 concentrations [49 ]were associated with alterations of weight or anthropometric parameters like body mass index, waist circumference, and waist-to-hip-ratio.

Weight was strongly associated, whereas blood pressure was only weakly related to TSH levels [43 ]and subclinical hypothyroidism was not associated with blood pressure at all [50]. This illustrates the differences of individual components of the MetS and their relation to TSH concentrations.

Few studies explored the association of TSH or fT3 with the incidence of MetS (and not just individual components). TSH levels were positively associated with the incidence of MetS, in some [41, 51], but not all studies [24]. However, the latter study examined elderly persons, and age alone as well as comorbidities may have independent effects on TSH and TH levels. Just recently, fT3 levels were also reported to be associated with the incidence of MetS [52].

Available epidemiological data point toward a relationship between TH status and MetS. However, the cited studies do not establish mechanistic links. The next part of this review will summarize available experimental data providing evidence for underlying mechanisms.

TH and MetS: Experimental Data

THs are of central importance for energy homeostasis and metabolism [53, 54]. As they target the same metabolic pathways known to be altered in MetS, we will summarize some aspects of the interactions of TH on energy homeostasis and substrate flux from experimental studies in order to provide a potential common basis for an understanding of TH effects on these components of the MetS, summarized in Fig. 1.

Hypothalamic Control of Lipid and Glucose Metabolism by TH

The arcuate nucleus (ARC) of the hypothalamus is a key center for the control of food intake and energy expenditure. It directly interacts with the hypothalamic control of the thyroid axis via direct projections to the thyrotropin-releasing hormone (TRH) regulating centres within the paraventricular nucleus (PVH) [55, 56]. Control of energy homeostasis within the ARC is achieved by 2 antagonistically acting groups of neurons, neuropeptide Y (NPY)/agouti-related peptide (AgRP) on the one side, and proopiomelanocortin (POMC)/cocaine and amphetamine regulated transcript on the other. Activation of POMC neurons induces the release of α melanocyte-stimulating hormone which activates melanocortin receptor subtypes 3 and 4 (MC3R and MC4R, respectively), subsequently stimulating hypothalamic satiety centers and the activity of the sympathetic nervous system (SNS) outflow to peripheral energy regulating organs. In contrast, AgRP and NPY positive neurons antagonize these anorexigenic action of POMC via direct inhibitory action of AgRP at the MC4R but also via the release of the transmitters NPY and γ-aminobutyric acid, both able to inhibit POMC neurons [57]. Leptin and ghrelin antagonistically modulate POMC and AgRP neurons. An increase of glucose concentrations within the physiological range stimulates TRH expression indicating a direct feedback [58]. These ex vivo and in vitro experiments fit well to the inhibition of preproTRH (and corticotropin-releasing hormone) in the PVH during fasting, a process again controlled by the ARC [59, 60]. In knock-out mice lacking either MC4R or NPY or both the drop of TRH, TSH, and peripheral TH could convincingly be attributed to NPY/AgRP whereas hepatic metabolism of T4 is governed by both MC4R and NPY [61]. High T3 appears to dose-dependently inhibit the expression of MC4R in the PVH and ARC by interaction with both of its receptors, TRα and TRβ [62]. T3 will be supplied at least to ARC AgRP positive neurons through the surrounding microglia which express Deiodinase type 2 (DIO2). T4 taken up from the blood is converted to T3 and transported via monocarboxylate transporter 8 (MCT8)-dependent transport to the neurons [63]. Microglial DIO2 is upregulated and stimulates local mitochondrial biogenesis through uncoupling protein 2 (UCP2) expression – a mechanism regarded to be as important as a memory function to regulate food intake...

Table of contents

• Cover Page
• Front Matter
• Metabolic Syndrome in Hypopituitarism
• Metabolic Complications of Acromegaly
• Metabolic Syndrome in Hyperprolactinemia
• Metabolic Syndrome in Thyroid Disease
• Metabolic Syndrome in Parathyroid Diseases
• Metabolic Syndrome in Cushing’s Syndrome Patients
• Metabolic Complications in Adrenal Insufficiency
• Metabolic Syndrome in Polycystic Ovary Syndrome
• Metabolic Syndrome in Male Hypogonadism
• The Metabolic Syndrome in Central Hypogonadotrophic Hypogonadism
• Author Index
• Subject Index
• Back Cover Page